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- PDB-3ccz: Thermodynamic and structure guided design of statin hmg-coa reduc... -

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Basic information

Entry
Database: PDB / ID: 3ccz
TitleThermodynamic and structure guided design of statin hmg-coa reductase inhibitors
Components3-hydroxy-3-methylglutaryl-coenzyme A reductase
KeywordsOXIDOREDUCTASE / CHOLESTEROL BIOSYNTHESIS / HMG-COA / NADPH / STATIN / Alternative splicing / Endoplasmic reticulum / Glycoprotein / Lipid synthesis / Membrane / Peroxisome / Polymorphism / Steroid biosynthesis / Transmembrane
Function / homology
Function and homology information


Cholesterol biosynthesis / PPARA activates gene expression / Activation of gene expression by SREBF (SREBP) / ubiquinone metabolic process / hydroxymethylglutaryl-CoA reductase (NADPH) / negative regulation of striated muscle cell apoptotic process / hydroxymethylglutaryl-CoA reductase activity / hydroxymethylglutaryl-CoA reductase (NADPH) activity / negative regulation of amyloid-beta clearance / positive regulation of stress-activated MAPK cascade ...Cholesterol biosynthesis / PPARA activates gene expression / Activation of gene expression by SREBF (SREBP) / ubiquinone metabolic process / hydroxymethylglutaryl-CoA reductase (NADPH) / negative regulation of striated muscle cell apoptotic process / hydroxymethylglutaryl-CoA reductase activity / hydroxymethylglutaryl-CoA reductase (NADPH) activity / negative regulation of amyloid-beta clearance / positive regulation of stress-activated MAPK cascade / sterol biosynthetic process / positive regulation of skeletal muscle tissue development / coenzyme A metabolic process / negative regulation of wound healing / negative regulation of insulin secretion involved in cellular response to glucose stimulus / peroxisomal membrane / isoprenoid biosynthetic process / myoblast differentiation / positive regulation of cardiac muscle cell apoptotic process / regulation of cholesterol biosynthetic process / coenzyme binding / cholesterol biosynthetic process / negative regulation of blood vessel diameter / negative regulation of protein secretion / negative regulation of MAP kinase activity / visual learning / protein phosphatase 2A binding / NADPH binding / response to nutrient / negative regulation of protein catabolic process / positive regulation of smooth muscle cell proliferation / protein tetramerization / regulation of lipid metabolic process / response to ethanol / positive regulation of ERK1 and ERK2 cascade / aging / endoplasmic reticulum membrane / endoplasmic reticulum / protein homodimerization activity / integral component of membrane
Hydroxymethylglutaryl-CoA reductase, class I/II / Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain superfamily / Hydroxymethylglutaryl-coenzyme A reductases signature 1. / Hydroxymethylglutaryl-coenzyme A reductase / Hydroxymethylglutaryl-coenzyme A reductases signature 2. / Hydroxymethylglutaryl-CoA reductase, N-terminal / Hydroxymethylglutaryl-coenzyme A reductases signature 3. / Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site / Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain superfamily / Hydroxymethylglutaryl-coenzyme A reductases family profile. ...Hydroxymethylglutaryl-CoA reductase, class I/II / Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain superfamily / Hydroxymethylglutaryl-coenzyme A reductases signature 1. / Hydroxymethylglutaryl-coenzyme A reductase / Hydroxymethylglutaryl-coenzyme A reductases signature 2. / Hydroxymethylglutaryl-CoA reductase, N-terminal / Hydroxymethylglutaryl-coenzyme A reductases signature 3. / Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site / Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain superfamily / Hydroxymethylglutaryl-coenzyme A reductases family profile. / Sterol-sensing domain of SREBP cleavage-activation / Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain superfamily / Sterol-sensing domain (SSD) profile. / Hydroxymethylglutaryl-CoA reductase, metazoan / Sterol-sensing domain / Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type
3-hydroxy-3-methylglutaryl-coenzyme A reductase
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsPavlovsky, A. / Sarver, R.W. / Harris, M.S. / Finzel, B.C.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme a reductase.
Authors: Sarver, R.W. / Bills, E. / Bolton, G. / Bratton, L.D. / Caspers, N.L. / Dunbar, J.B. / Harris, M.S. / Hutchings, R.H. / Kennedy, R.M. / Larsen, S.D. / Pavlovsky, A. / Pfefferkorn, J.A. / Bainbridge, G.
Validation Report
SummaryFull reportAbout validation report
History
DepositionFeb 26, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
B: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
C: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
D: 3-hydroxy-3-methylglutaryl-coenzyme A reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)192,41312
Polymers189,9184
Non-polymers2,4958
Water22,2671236
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area25380 Å2
ΔGint-170.8 kcal/mol
Surface area54750 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)82.862, 135.655, 83.148
Angle α, β, γ (deg.)90.00, 97.16, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein/peptide
3-hydroxy-3-methylglutaryl-coenzyme A reductase / HMG-CoA reductase


Mass: 47479.551 Da / Num. of mol.: 4 / Fragment: CATALYTIC DOMAIN (RESIDUES 441-875) / Mutation: M485I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HMGCR / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 STAR
References: UniProt: P04035, hydroxymethylglutaryl-CoA reductase (NADPH)
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4 / Sulfate
#3: Chemical
ChemComp-5HI / (3R,5R)-7-[2-(4-fluorophenyl)-4-{[(1S)-2-hydroxy-1-phenylethyl]carbamoyl}-5-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxyheptanoic acid


Mass: 527.584 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H34FN3O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1236 / Source method: isolated from a natural source / Formula: H2O / Water

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.44 Å3/Da / Density % sol: 49.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: protein 15-20 mg/ml, Ligand (saturated),PEG 4000, MgCl2 0.2M, Tris-HCL pH8 0.1M, 7-10 days, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 9, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionRedundancy: 3.7 % / Av σ(I) over netI: 26.4 / Number: 694736 / Rmerge(I) obs: 0.041 / Χ2: 0.85 / D res high: 1.7 Å / D res low: 50 Å / Num. obs: 187138 / % possible obs: 93.6
Diffraction reflection shell

Diffraction-ID: 1

Highest resolution (Å)Lowest resolution (Å)% possible obs (%)Rmerge(I) obsChi squaredRedundancy
3.665090.10.0380.3413.6
2.913.6699.10.0370.7593.8
2.542.9199.70.0390.8033.8
2.312.5499.60.0410.8373.8
2.142.3199.30.0460.9013.8
2.022.1499.10.0540.9753.8
1.912.0298.90.0670.9413.8
1.831.9198.70.0850.9363.8
1.761.8384.80.0950.9973.3
1.71.7666.90.1161.0223.1
ReflectionResolution: 1.7→50 Å / Num. obs: 187138 / % possible obs: 93.6 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.041 / Χ2: 0.845 / Net I/σ(I): 26.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.7-1.763.10.116133301.02266.9
1.76-1.833.30.095169250.99784.8
1.83-1.913.80.085196810.93698.7
1.91-2.023.80.067196960.94198.9
2.02-2.143.80.054197900.97599.1
2.14-2.313.80.046198670.90199.3
2.31-2.543.80.041198200.83799.6
2.54-2.913.80.039199400.80399.7
2.91-3.663.80.037198880.75999.1
3.66-503.60.038182010.34190.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.004data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→50 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.92 / SU B: 2.616 / SU ML: 0.086 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.131 / ESU R Free: 0.122 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.257 3756 2 %RANDOM
Rwork0.232 ---
Obs0.233 187015 93.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 25.234 Å2
Baniso -1Baniso -2Baniso -3
1-0.41 Å20 Å20.85 Å2
2--0.26 Å20 Å2
3----0.46 Å2
Refinement stepCycle: LAST / Resolution: 1.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12061 0 172 1236 13469
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0050.02112405
r_bond_other_d0.0010.0211484
r_angle_refined_deg0.861.98616764
r_angle_other_deg1.155326781
r_dihedral_angle_1_deg4.39151614
r_chiral_restr0.0490.21929
r_gen_planes_refined0.0020.0213819
r_gen_planes_other0.0010.022291
r_nbd_refined0.1490.22571
r_nbd_other0.1810.214173
r_nbtor_other0.0760.27500
r_xyhbond_nbd_refined0.0710.21053
r_symmetry_vdw_refined0.0880.29
r_symmetry_vdw_other0.1380.234
r_symmetry_hbond_refined0.0190.29
r_mcbond_it0.231.58015
r_mcangle_it0.433212828
r_scbond_it0.49234390
r_scangle_it0.894.53936
LS refinement shellResolution: 1.699→1.743 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.322 194
Rwork0.289 9358
All-9552

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